Identifying genetic variants underlying the risk for complex disorders such as depression is extremely difficult. To complement linkage and association studies of depression, we propose a genetic association study of Neuroticism. The genetics of Neuroticism overlaps significantly with that of depression, but it constitutes a quantitative trait that can be measured in a population sample. Neuroticism is measured with the psychometrically sound, validated NEO personality inventory. Our sample consists of about 1500 subjects in about 500 families ascertained through a hypertensive proband but unselected otherwise, and about 200 hypotensive controls. More than half of the subjects have also been administered the NEO-PI, and all have given blood for genetic DMA analysis. With the first 470 subjects, we found two genetic variants associated with Neuroticism, which were replicated by other laboratories and also found associated with affective disorder in other studies. These findings confirm our underlying hypothesis that identification of genetic variants affecting Neuroticism scores will be relevant for affective disorders. In addition, a whole genome scan has been performed on our sample and will be analyzed for linkage to personality traits, including Neuroticism. In this pilot grant, we propose to continue candidate gene analysis. Candidate genes will be informed by our preliminary data, ongoing microarray analyses, the literature, and linkage analyses. We will start with candidate genes involved in the serotonin system due to our preliminary data. SNPs in these candidate genes will be either known functional (coding or promoter) variants, or selected from the HAPMAP. DNA analysis will be performed with a novel, multiplex (15-30 SNPs) genotyping system and will be compared to commercial genotyping methods for optimization and error rate determination. The nuclear family structure allows both population-based and family-based association studies to be carried out. A variance component model-based association test called QTDT, which is able to account for familial resemblance, is an ideal tool for this type of analysis Haplotype analyses are reported to be more informative than single marker analysis in association studies, and we will use generalized linear models to estimate haplotype effects. At the end, we will compare the results obtained from different association tests, and follow up on the most interesting signals. It is anticipated that this R21 will lead to a more thorough, genome-wide genetic study of Neuroticism in this valuable sample.